Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Cell Biology, MOSAIC ANALYSIS, DOUBLE MARKERS, NEUROGENESIS, STEM, EXPRESSION, DIFFERENTIATION, MEDULLOBLASTOMA, SPECIFICATION, GLIOGENESIS, INTEGRATION, Notch signaling, human cerebellar organoids, mouse cerebellum, neural stem cells, neuronal diversity, Cell Differentiation, Cerebellum, Humans, Neurons, Receptors, Notch, 0601 Biochemistry and Cell Biology, 1116 Medical Physiology, 31 Biological sciences

Abstract:

Brain neurons arise from relatively few progenitors generating an enormous diversity of neuronal types. Nonetheless, a cardinal feature of mammalian brain neurogenesis is thought to be that excitatory and inhibitory neurons derive from separate, spatially segregated progenitors. Whether bi-potential progenitors with an intrinsic capacity to generate both lineages exist and how such a fate decision may be regulated are unknown. Using cerebellar development as a model, we discover that individual progenitors can give rise to both inhibitory and excitatory lineages. Gradations of Notch activity determine the fates of the progenitors and their daughters. Daughters with the highest levels of Notch activity retain the progenitor fate, while intermediate levels of Notch activity generate inhibitory neurons, and daughters with very low levels of Notch signaling adopt the excitatory fate. Therefore, Notch-mediated binary cell fate choice is a mechanism for regulating the ratio of excitatory to inhibitory neurons from common progenitors.